Beginning in 1982, a subset of the Pima Indians living in Southwestern Arizona, a population with one of the highest prevalence rates of obesity and type 2 diabetes mellitus (T2DM), has been studied to determine the etiologic risk factors that predispose non-diabetic individuals to develop T2DM. Within this high risk population, it is possible to identify subgroups of individuals at an even higher risk for T2DM, including persons whose mothers were diabetic during pregnancy. We use DXA scanning to determine body composition; MRI scanning to determine fat distribution; a 75-g oral glucose tolerance test to assess glucose tolerance; a hyperinsulinemic-euglycemic glucose clamp to assess insulin sensitivity; a 5-step hyperglycemic infusion to assess insulin secretory function. In the past year we have: a) established that high levels of non specific markers of inflammation (WBC, ALT) and low levels of adiponectin (an anti inflammatory adipokine) predict development of T2DM in Pimas; b) continued a study of insulin secretory function in individuals whose mothers had diabetes during pregnancy, individuals whose fathers developed diabetes at an early age and individuals whose parents developed diabetes at a late age or did not develop diabetes (ongoing); c) continued a study to establish the pathophysiological link between large subQ abdominal adipocytes and risk of T2DM (ongoing); d) designed a novel clinical trial to test the hypothesis that short term anti inflammatory treatment will improve insulin sensitivity in non-diabetic individuals at high risk for the development of T2DM (to be initiated later this year)